Compounds View

Input/Option

Description

Compound

A drop-down. Selects the required compound. Options are populated based on compounds already added to the project. If no compounds have been added, this will be blank, and panels below will be disabled.

• Add – Adds a compound to the project - activates the Enter Compound name: input box to name the new compound.

• AP Import – navigates to the ADMET Predictor® module.

• Rename – Renames the currently selected compound.

• Copy – Copies the currently selected compound - activates the Copy the Compound [ ] to: input box to name the new compound.

• Delete – Deletes the currently selected compound.

Input/Option

Description

Formula

The chemical formula for the selected compound.

Note: The formula is provided for your convenience only. GPX™ does not require or use this information for any calculation purposes.

Molecular Weight

The molecular weight for the selected compound. The default value is 100 g/mol. Both the value and the units (g/mol, kg/mol) can be edited.

Melting Point

The melting point for the selected compound. The default value is 0 °C. Both the value and the units (°C, K, °F) can be edited.

Diffusion Coefficient

The diffusion coefficient for the selected compound, defined as the proportionality constant between the time rate of change of concentration at a point and the spatial variation of the concentration at that point. It is representative of how rapidly molecules in solution move away from the surface of a dissolving particle into the free stream and is a function of the viscosity of the surrounding fluid. As such, it is dependent on temperature and surfactant effects; however, it is treated as a constant in GPX™. The default value is 7.5e-06 cm2/s. Both the value and the units (cm2/s, mm2/s, m2/s) can be edited.

Calculate Diffusion Coefficient

If the diffusion coefficient is unknown, but the molecular weight is entered clicking this button will calculate an estimated value based on the molecular weight.

Display Structure

A toggle. When the toggle is on, the structure is displayed, turning it off hides the displayed structure.

Image Source

Indicates the source of the displayed structure.

Input/Option

Description

Form Name

If there are two or more solid forms of the selected compound with different solubilities (either two different crystalline forms or a mixture of an amorphous and a crystalline form) or the compound might precipitate in a solid form with different solubility than the administered compound, then this value identifies each different form. The default value is Form 1. Subsequent forms will be Form 2, Form 3, etc. The Form Name cannot be edited.

Solubility (mg/mL)

The measured or estimated solubility of the selected form. The default value is 1 mg/mL. Both the value and the units (mg/mL, mg/L) can be edited.

pH

The pH at which the solubility of the selected form was measured or estimated. This value is not applicable for intrinsic solubilities (see below).

The value can be edited.

Temperature

The temperature at which the solubility of the selected form was measured or estimated. The default value is 37°C. Both the value and the units (°C, K, °F) can be edited.

Temperature Corrected Solubility (mg/mL)

Calculates the solubility at body temperature (37°C) based on the melting point, the measured solubility and the temperature at which the solubility was measured, as entered in the Compound view.

Intrinsic Solubility

A toggle. Off by default. Controls whether the solubility value entered is considered an intrinsic solubility (solubility of the pure neutral species). Activating the toggle removes the associated pH. The solubility value is still used to define the pH solubility curve, but the point will not appear on the plot.

Density

The average density (in g/mL) of the particles of the indicated form (after disintegration) in the dosage form. The default value is 1.2 g/mL.

The value can be edited.

Estimate Tension

A button.

Applicable for Precipitation models. Uses the GastroPlus® built-in correlation between the interfacial tension and native solubility of the drug ¹ to estimate interfacial tension if a value is not available from another source. The correlation is applicable only for low solubility compounds.

To estimate the interfacial tension, click the Estimate button and the Interfacial Tension (J/m3) column will be populated for the specified Form.

Interfacial Tension (J/m2)

Applicable for Precipitation models. The interfacial tension between the crystal and surrounding solution. The value is used in the Kelvin equation to adjust solubility for the particle size effect. The default value is 0 J/m2.

Both the value and the units (J/m2, mJ/m2) can be edited.

Use For Precipitation

A toggle. Turned on by default for Form 1. Controls which Form will be used to define the solubility of any precipitate.

Add

Adds a Form to the solubility table for the selected compound.

Copy

Copies the currently selected Form.

Hold [CTRL]-key and click to highlight a row to copy.

Delete

Deletes the currently selected Form.

Hold [CTRL]-key and click to highlight a row for deletion.

Calc. Native pH

For ionized compounds, if you are using the solubility measured in pure water by adding drug compound until it is saturated, then the pH of the resulting solution is changed by the addition of the drug. This pH is called the “native pH”.

Clicking the Calc. Native pH button, will cause GPX™ to calculate the native pH for your compound if the pKa’s have been entered in the Dissociation (pKa) panel.

Input/Option

Description

Polymorphic Form

A drop-down. Selects the form for which biorelevant solubilities (and thus solubilization ratio) will apply.

Media options

• SGF. Simulated Gastric Fluid

• FaSSIF. Fasted State Simulated Intestinal Fluid

• FeSSIF. Fed State Simulated Intestinal Fluid

• User. A User-defined biorelevant media other than SGF, FaSSIF, or FeSSIF.

Note:  If solubilities in three different media with varying bile salt concentrations are available, then the User option for biorelevant solubility provides an option for a more accurate calculation of the bile salt solubilization ratio.

pH

The final pH of the indicated medium.

The value can be edited to reflect the in vitro assay conditions used to generate the solubility in the given media.

Bile Salt Concentration

The bile salt concentration, in mmol/L, for the indicated medium.

The value can be edited to reflect the in vitro assay conditions used to generate the solubility in the given media.

Solubility

The in vitro solubility, in mg/mL, of the form in the given medium.

The value can be edited.

Selected

A toggle. Controls whether the indicated biorelevant solubility will be included in the calculation of the solubilization ratio. On by default.

Note that if the solubility is 0, the value will not be used in the calculation of solubilization ratio, even if this toggle is on.

Input/Option

Description

Additional Solvents

Parameters for additional solvents for use with suspension dosage formulations.

Solvent

The name of the additional solvent. Solvents are added to the table automatically when clicking the Add button.

Molecular Weight

The molecular weight, in g/mol, of the solvent. The value can be edited.

Density

The density, in mg/mL, of the solvent. The value can be edited.

Add

Adds a new solvent to the table.

Delete

Deletes the selected solvent from the table.

Hold [CTRL]-key and click on any cell in a row to highlight a row for deletion.

Additional Solubilities for the Compounds in the Solvent(s)

Parameters for the solubility of the selected compound in the additional solvent. If there are multiple forms (polymorphs) of the compound, each form will have a line in this table.

Solvent

A drop-down. Selects the solvent for which information will be entered. This drop-down is automatically populated with the solvents in the Additional Solvents table.

Form Name

The name of the compound form for which solubility information will be entered. Form Names are added to the table automatically when clicking the Add button and must match those added in the Solubility panel.

Solubility

The solubility, in mg/mL, of the compound in the additional solvent. The value can be edited.

pH

The final pH of the solution in which the solubility was measured. The value can be edited.

Temperature

The temperature, in °C, at which the solubility was measured. The value can be edited.

Solubilizers

Parameters for solubilizers for use with oral dosage formulations.

Solubilizer

The name of the solubilizer. Solubilizers are added to the table automatically when clicking the Add button.

Molecular Weight

The molecular weight of the solubilizer in g/mol. The value can be edited.

Add

Adds a new solubilizer to the table.

Delete

Deletes the selected solubilizer from the table.

Hold [CTRL]-key and click to highlight a row for deletion.

Rename

Renames the selected solubilizer.

Hold [CTRL]-key and click to highlight a row for renaming.

Input/Option

Description

Acid/Base

A drop-down. Selects the type of titratable group: Acid, Base, or Mixed.

Note that Mixed pK_a values are predicted by ADMET Predictor®. Manually added pK_a values cannot be set to Mixed.

The default value for user-added pK_a values is Acid.

pKa

The corresponding pK_a of the titratable group. The default value is 7.

Solubility Factor

The ratio of the solubility of the ionized state of the compound to the solubility of the un-ionized state for the pK_a. The default value is 1.

Solubility Data

A drop-down. Selects the Form to which the solubility data corresponds (both reference and observed).

Observed Data Profile

Enables selection of Solubility Data that has been entered in the Observed Data View to be used to fit the pK_a values and Solubility Factor for a Compound and Form. The data selected is shown on the graph to the right, with the legend name taken from the Series Name for the data.

Note: This selection is not saved. It will need to be reselected when the project is reopened to allow the Current model to be compared to the solubility profile.

Group Name

A drop-down. Selects the relevant Group Name that contains the observed Solubility data.

Series Name

A drop-down. Selects the relevant Series Name in the selected Group that contains the observed Solubility data.

Enable pK_a Fitting

A toggle. Turn on to enable the pK_a values and Solubility Factors to be fitted to the observed data.

Optimization Initial Step

The initial step size used for optimization. Set to 0.05 by default. This value can be edited.

Selection Method

A toggle. Switched to Auto by default meaning the program will determine the pK_as and Solubility Factors to optimize. Switching to User enables user selection of the pK_as and Solubility Factors to optimize.

Fit pKa toggle

A toggle for each pK_a value in the table – if User is chosen as the Selection Method these will be enabled. Turn on to optimize the particular pK_a value displayed as the toggle label. All are turned off by default.

Fit Solubility toggle

A toggle for each Solubility Factor in the table – if User is chosen as the Selection Method these will be enabled. Turn on to optimize the particular Solubility Factor displayed as the toggle label. All are turned off by default.

Fit

Click to fit the pK_a values and Solubility Factors to the observed solubility data. The alternative Solubility vs pH curve is displayed in green on the plot. The optimized values for the pK_as and Solubility Factors are displayed as the toggle label.

Accept Fit

Click to accept the fitted pK_a values and Solubility Factors

Plot

The plot allows the Solubility vs pH curve to be visualized, together with the reference solubility and any observed solubility data. The fitted solubility profile will also be displayed prior to the fit being accepted. Clicking on the series names on the left of the plot displays only the series in green. To select multiple for display hold [CTRL]-key and click.

Input/Option

Description

LogD [ ] at pH [ ]

• The LogD of the compound at the indicated pH

LogP [ ]

• The LogP of the neutral species of the compound

The default value is 1.

Correction factors

Settings for the correction factors used in interconverting between LogD and LogP based on the prevalence of different charged species of the compound across the pH range.

Use Automatic Empirical Factors

A toggle. Indicates whether built-in correction factors should be used for the empirical LogD model. Toggled on by default. Toggling this off enables editing of the empirical correction factors in the table below.

Correction Factors Table

The Correction Factors used for empirical and structural LogD models, for the Anionic, Cationic, and Zwitterionic species. Empirical correction factors can be edited if Use Automatic Empirical Factors is toggled off. Structural correction factors are generated only if the compound is imported through ADMET Predictor® and cannot be edited.

Number of Acidic Groups, Formal Charge, and Fraction Zwitterionic

Parameters generated by ADMET Predictor® for applying the structural model correction factors. If the compound was not imported through ADMET Predictor®, these will be 0 or -1. These values cannot be edited.

Model

A drop-down. Selects whether the Structural or Empirical LogD model will be used for this compound. The structural model only applies to compounds imported through ADMET Predictor®.

Plot

The plot allows the LogD vs pH curve to be visualized and to observe the impact of using the Structural or Empirical LogD model. Clicking on the series names on the left of the plot displays only the series in green. To select multiple for display hold [CTRL]-key and click.

Input/Option

Description

Source

The source(s) for input permeability values, from in vitro P_app or in vivo P_eff experiments, or user-defined permeability correlations (see below). The source also dictates which correlation, if any, will be used to convert to the P_eff during simulation.

If the source is set to Direct Entry, no conversion will be applied, regardless of the simulated species–the input permeability will be used directly in the simulation.

Input Permeability

The permeability for the selected compound and permeability source.

The value can be edited. The units (cm/s, nm/s, µm/s) can be changed in the column header.

Adson

Parameters for the Adson paracellular model

Automatically recalculate from molecular mass

A toggle. Turned on by default. Indicates whether the Adson effective spherical radius will be calculated from the molar mass of the compound, as input in the Molecular Properties panel. Turning the toggle off enables the Adson Effective Spherical Radius to be edited (see below).

Effective Spherical Radius

The molecular radius utilized by the Adson model for paracellular permeability calculations.

If “Automatically recalculate from molecular mass” is toggled on, this box displays the calculated value. Toggling “Automatically recalculate from molecular mass” off enables editing of the value and the units (A, nm, µm).

Zhimin

Parameters for the Zhimin paracellular model

Hydrodynamically Equivalent Spherical Radius and Mean Projected Radius

The radii utilized by the Zhimin model for paracellular permeability. These parameters are calculated by ADMET Predictor^® upon structure import and will be invalid for compounds not imported through ADMET Predictor^®.

These values can be edited. If the values are zero, the Zhimin model will not be available for use in the Simulations view (see Permeability sub-panel).

Input/Option

Description

User Permeability Correlation

A drop-down. Selects the current user-defined correlation to view and/or edit. Newly added user-defined correlations appear in this menu after adding.

Compound

The name of the reference compound for which experimental and human permeability measurements are available.

Experimental Permeability

The in vitro P_app measurement, which serves as the independent variable in the correlation.

Values of 0 will be ignored when solving the correlation.

Human Permeability

The in vivo human P_eff measurement, which serves as the dependent variable in the correlation.

Established P_eff values for a set of standard reference compounds is provided by default (see ‘Load from Defaults’ below).

Source

The source of the permeability data. This is provided for the default reference compounds. Users may enter their own references for their data in this column. This field is for record-keeping purposes.

Add/Delete

Add compounds to, or delete compounds from, the table.

Load from Defaults

Populates the table with 33 standard reference compounds with established human P_eff values. Experimental permeability will be 0 for all of these compounds and must be filled in by the user.

Solve

Solves the correlation functions using the data in the table.

Spearman’s Rank Correlation Coefficient:

Statistical parameter indicating the degree of association between the rank orders of Experimental Permeability and Human Permeability. This value is calculated upon fitting the correlation and cannot be edited.

Correlation Function

Indicates the correlation equation type: linear or log-linear.

Function

Displays the respective equations with fit coefficients.

Rsq, MAE, SEP, AIC

Statistical parameters indicating the goodness-of-fit of each equation type.

Select

A toggle which indicates which equation will be used when the correlation is applied. By default, the equation with the lowest AIC will be selected. The selection can be edited.

Input/Option

Description

Species

The species to which the metabolism kinetics apply.

Enzyme

The enzyme for the metabolism. Default enzymes will vary based on the species. For adding custom enzymes, see Custom below.

Phenotype

The phenotype for the enzyme for this metabolism. It is possible to have individual metabolism entries for each phenotype of an enzyme.

Location

The model-level location for the metabolism (e.g. Enterocytes, Compartmental Liver, PBPK Tissue, etc.).

V_max

The V_max for the metabolism, in mg/s for Enterocytes, Lumen, and Compartmental Liver locations, and mg/s/mg for PBPK Tissue and other locations. the value and the units (mg/s, mg/min, mg/s/mg, mg/min/mg, mg/s/g, mg/min/g) may be edited.

K_m

The K_m for the metabolism. Both the value and the units (mg/L, µg/mL, mg/mL) can be edited.

Metabolite

The metabolite generated by this metabolism, used for metabolite tracking. Set to None by default, which will not track metabolites.

Metabolites must first be added as additional compounds, after which they can be selected here.

Metabolite:Parent

The ratio of metabolite molecules formed for each parent molecule metabolized. The default value is 1. This can be increased for substrates that are cleaved into symmetrical metabolites.

In Vivo V_max Scale Factor

A scale factor for V_max. The V_max value will be multiplied by the scale factor when the Simulation is run to yield the final value used in the simulation. This is useful for exploring the effect of changing V_max without having to change the baseline value. The Scale Factor is also the parameter which is permuted by Optimization (see Optimization View).

In Vivo K_m Scale Factor

A scale factor for K_m. The K_m value will be multiplied by the scale factor when the Simulation is run to yield the final value used in the simulation. This is useful for exploring the effect of changing K_m without having to change the baseline value. The Scale Factor is also the parameter which is permuted by Optimization (see Optimization View).

Add

Add a new row to the enzyme table. After adding the row, the species, enzyme, phenotype, etc. can be selected. Only default enzymes, or previously added custom enzymes, may be selected using this method.

Custom

Add a custom enzyme for an indicated species. Once the custom enzyme is created, it will be added automatically as a row to the table. It will also be available thereafter in the enzyme drop-down for selection.

Expression of custom enzymes must also be added in the Physiologies (gut enzymes) or Pharmacokinetics (PBPK enzymes) views (see sections Physiology sub-panel and Pharmacokinetics View).

Clear

Clear the entire table.

Delete

Delete the selected row from the table. Hold [CTRL]-key and click to highlight a row for deletion.

Input/Option

Description

Species

The species to which the transporter kinetics apply.

Transporter

The transporter for the transport. Default transporters will vary based on the species. For adding custom transporters, see Custom below.

Location

The model-level location for the transport (e.g. Enterocytes, PBPK Tissue)

V_max

The V_max for the transport, in mg/s for Enterocytes and mg/s/mg for PBPK. Both the value and the units (mg/s, mg/min; mg/s/mg, mg/min/mg, mg/s/g, mg/min/g) can be edited.

K_m

The K_m for the transport. Both the value and the units (mg/L, µg/mL, mg/mL) can be edited.

In Vivo V_max Scale Factor

A scale factor for V_max. The V_max value will be multiplied by the scale factor when the Simulation is run to yield the final value used in the simulation. This is useful for exploring the effect of changing V_max without having to change the baseline value. The Scale Factor is also the parameter which is permuted by Optimization (see Optimization View).

In Vivo K_m Scale Factor

A scale factor for K_m. The K_m value will be multiplied by the scale factor when the Simulation is run to yield the final value used in the simulation. This is useful for exploring the effect of changing K_m without having to change the baseline value. The Scale Factor is also the parameter which is permuted by Optimization (see Optimization View).

Add

Add a new row to the transporter table. After adding the row, the species, transporter, location, etc. can be selected. Only default transporters, or previously added custom transporters, may be selected using this method.

Custom

Add a custom transporter for an indicated species. Once the custom transporter is created, it will be added automatically as a row to the table. It will also be available thereafter in the transporter drop-down for selection.

Expression of custom transporter must also be added in the Physiologies (gut transporters) or Pharmacokinetics (PBPK transporters) views (see Physiology sub-panel and Pharmacokinetics View).

Clear

Clear the entire table.

Delete

Delete the selected row from the table.